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of 48 patients diagnosed with OHSS. The patients were treated with outpatient
transvaginal culdocentesis and rehydration with intravenous crystalloids and
albumin every one to three days until resolution of symptoms or hospitaliza-
tion was required. No complications occurred from outpatient treatment, and
91.6% of patients avoided hospitalization. The authors concluded that
outpatient treatment, consisting of culdocentesis, intravenous rehydration and


200
201
HOSPITALIZATION OF PATIENTS WITH SEVERE OHSS




albumin, minimized the need for hospitalization in these patients. The patient
should be instructed to report to the hospital if she develops dyspnea, if the
volume of urine is diminished or upon development of any unusual symptoms,
such as leg swelling, dizziness, numbness and neurological problems.
The question whether severe OHSS should be managed on an outpatient
basis depends on the classi¬cation and de¬nition of severity, comfort of the
physician, and compliance and reliability of patients. Severe OHSS grade A is
managed on an outpatient basis by the aspiration of ascitic ¬‚uid, administra-
tion of intravenous ¬‚uids and the evaluation of all biochemical parameters.
Shrivastav et al. (1994) reviewed their experience in the management of
18 patients who developed severe OHSS. The ¬rst group of eight patients was
managed conservatively with hospitalization, intravenous hydration and
supportive therapy. The average duration of hospitalization was seven days
and the patients were uncomfortable throughout. The second group, which
consisted of 10 patients, was managed on an outpatient basis with early
ultrasound guided paracentesis. While the patients were hydrated intra-
venously, 1À3 liters were removed over 2À3 hours. The original hospitalization
was for 6À7 h and no inpatient stay was required. The patient™s symptoms were
promptly relieved and none of the patients in this series required retapping.
Shrivastav et al. (1994) suggested that day care management with abdominal
paracentesis is a simple, safe and effective method, and is more acceptable for
patients. However, I have to emphasize that each center should adopt the
policies that best serve their patients and take into account their facilities™
expertise and resources.
A more recent report included 139 patients who developed severe OHSS
during 8311 IVF cycles from 1998 to 2004 (Gustofson et al., 2005). Aggressive
outpatient management of severe OHSS with early paracentesis, intravenous
¬‚uid hydration, antiemetics, and DVT prophylaxis minimized the need for
hospital admission. Therefore, there has been a trend toward the use of
outpatient management that has gradually increased over the last decade.


HOSPITALIZATION OF PATIENTS WITH SEVERE OHSS

Patients with severe OHSS grade B and C are admitted to hospital for
treatment (Rizk and Aboulghar, 1999) (Figure VIII.1). Hospitalization should

Fig. VIII.1: Indications for hospitalization in OHSS
202 TREATMENT OF OVARIAN HYPERSTIMULATION SYNDROME




Fig. VIII.2: Management of OHSS




be considered if one or more of these symptoms or signs are present (Practice
Committee for the American Society for Reproductive Medicine, 2003)
(Figure VIII.2).


Clinical and Biochemical Monitoring in Hospital
The patient™s general condition requires regular assessment, with documen-
tation of vital signs, together with daily weight and girth measurement
(Rizk, 1993). Strict ¬‚uid balance recording is needed, particularly of urine
output.
Biochemical monitoring should include serum and electrolytes, renal and
liver function tests, a coagulation pro¬le and blood count (Rizk, 2001, 2002).
Serum and urinary osmolarity and urinary electrolyte estimation may be
required as the severity of the disease increases. Respiratory compromise and/or
signi¬cant deterioration in renal function require evaluation of blood gases
and acid-base balance. The frequency of these investigations will depend on the
severity of the condition.
Ultrasonographic examination provides accurate assessment of ovarian
size and the presence or absence of ascites, as well as pleural or pericardial
effusions (Rizk and Aboulghar, 1991). In addition, it will help in the diagno-
sis of intra- or extrauterine pregnancy as well as multiple or heterotopic
pregnancy (Rizk and Nawar, 2004). Chest X-ray will also provide information
203
MEDICAL TREATMENT




on the presence of hydrothorax. Assay of b-hCG will help to diagnose
pregnancy as early as possible.


MEDICAL TREATMENT
Circulatory Volume Correction
The main line of treatment is correction of the circulatory volume and
electrolyte imbalance (Rizk and Aboulghar, 1999). Every effort should be
directed towards restoring a normal intravascular volume and preserving
adequate renal function (Rizk and Nawar, 2004). Whelan and Vlahos (2000)
recommended starting with 1 l of IV normal saline and assessing change in
urine output and hematocrit response after 1 h. If urine output response is
adequate and hematocrit normalizes, switch to dextrose 5% normal saline and
maintain at the rate of 125 to 150 ml per hour while monitoring very closely
every 4 h. If urine output is inadequate in response to ¬‚uid bolus and the
hematocrit does not re¬‚ect a change toward euvolumia, IV crystalloid may
be stopped and IV albumin administered; 200 ml of a 25% solution admin-
istered at 50 ml/h over 4 h. One concern with using plasma expanders is that
the bene¬cial effect is transitory before their redistribution into the extra-
vascular space, further exacerbating ascites formation (Rizk and Aboulghar,
1991; Kissler et al., 2001). Dextran, mannitol and fresh frozen plasma have also
been used.
Hydryoxyethyl starch (HES) has the advantage of a non-biologic origin
and high molecular weight 200À1000 kDa vs. 69 kDa for albumin. Abramov
et al. (2001) compared the ef¬cacy and safety of 6% HES and human
albumin as colloid solutions for treatment of 16 patients with severe OHSS.
They observed a higher urine output, fewer paracenteses and shorter
hospital stays with HES (Table VIII.1). Gamzu et al. (2002) compared
HES 10% and Haemaccel and found no clinical advantage for the HES
(Table VIII.2). A recent case report in which a patient experienced rapid
recovery following treatment with 10% HES was reported by Rabinerson et al.
(2001). We agree with Delvigne and Rozenberg (2003) that larger prospective
randomized controlled studies are needed before de¬nite conclusions can be
drawn.


Electrolyte Replacement
Delvigne et al. (1993) observed electrolyte disorders in 54.6% of 128 cases of
OHSS; 24.2% of these were related to potassium and 22.2% were related to
sodium. Similarly, hyponatremia was observed in 56% of patients (Fabregues
et al., 1999). Appropriate intravenous solutions administered according to
protocol in the previous section will correct most electrolyte imbalances; if
hypokalemia is signi¬cant, a cation exchange resin may be needed (Rizk and
Aboulghar, 2005). Sodium and water restriction were advocated by Shapiro
et al. (1977) and Haning et al. (1985), but Thaler et al. (1981) found no change
204 TREATMENT OF OVARIAN HYPERSTIMULATION SYNDROME




Table VIII.1 Controlled cohort study to compare the ef¬cacy of 6%
hydroxyethyl starch and human albumin for treatment of severe OHSS
Reproduced with permission from Abramov et al. (2001). Fertil Steril 75:1228À30

Human albumin Hydroxyethyl starch
Variable (n ¼ 10) group (n ¼ 6)

Baseline characteristics
28.1 + 8.9 29.4 + 7.4
age (years)
6164 + 1418 9.080 + 2450
Estradiol level on day of HCG
Administration (pg/ml) 10 (100) 6 (100)
ascites (%) 2 (20) 1 (17)
pleural effusion (%) 4 (40) 6 (100)
10.7 + 3.4 10.5 + 3.8
gastrointestinal symptoms (%)
ovarian diameter 1 (10) 1 (16)
42 + 3.6 43 + 7
oliguria
3300 + 310 3150 + 270
hematocrit (%)
daily ¬‚uid intake (ml)*
2557 + 1032 3580 + 1780
Patient outcome
daily urine output (ml)** 8 (80) 2 (33)
2300 + 230
abdominal paracentesis (%) 1930
total ¬‚uid aspirated per patient (ml) 2 (20) 0
pleurocentesis (%)
19.0 + 8.2 15.7 + 5.7
hospital stay (days)
conception 7 (70) 4 (67)
miscarriage 2 (28) 1 (17)
congenital malformation 0 0

Values are means + SD or percentages of patients
* Including oral and intravenous hydration
** During the ¬rst ¬ve days of hospitalization




in the patient™s weight, abdominal circumference or peripheral edema when
sodium and water were restricted. Therefore, salt and water restriction are not
widely advocated.


Anticoagulant Therapy
Anticoagulant therapy is indicated if there is clinical evidence of thrombo-
embolic complications (Rizk et al., 1990a) or laboratory evidence of hyper-
coagulability (Rizk, 1993a). Arterial and venous thromboses are the most
common serious complications of OHSS.
205
MEDICAL TREATMENT




Table VIII.2 Hydroxyethyl starch and Haemaccel for the correction of
circulatory volume depletion in OHSS
Reproduced with permission from Gamzu et al. (2002). Fertil Steril. 77:1302À03

Characteristic Hydroxyethyl starch (n ¼ 20) Haemaccel (n ¼ 20)

1020 + 390 960 + 650
Reduction in body weight (g)
7 + 0.8 7 + 1.1
Reduction in hematocrit (%)
Reduction in leukocyte (‚10 000 cells ml) 4.7 + 0.6 4.4 + 0.6
1336 + 226 1217 + 187
Increase in urine volume (ml)
5.4 + 0.6 5.1 + 0.3
Duration of hospitalization

Values are the mean (+SD). There were no statistically signi¬cant differences between the values
for the two groups of women



Duration of Anticoagulation
The duration of anticoagulant administration is also debatable (Delvigne,
2004; Rizk and Aboulghar, 2005). Some investigators have reported late
thrombosis up to 20 weeks post transfer, and many investigators are in favor of
maintaining heparin therapy for some weeks (Serour et al., 1998; Delvigne,
2004).


Anticoagulant Prophylaxis
Preventative treatment with heparin should be used whenever there is a
thromboembolic risk (Delvigne and Rozenberg, 2003; Rizk and Aboulghar,
2005; Rizk et al., 1991a). However, what constitutes high risk for thrombo-
embolism? In cases of severe OHSS, the following situations are recognized
as indicating an increased risk of thromboembolism: immobilization,
compression of pelvic vessels by large ovaries or ascites, thrombophilias and
hyperestrogenemia (Rizk, 2001, 2002). Prevention using mobilization and
antithrombosis stockings are insuf¬cient, as thrombosis may occur at all
locations and may be systemic in nature.
Prophylaxis with heparin remains debatable for two reasons (Delvigne and
Rozenberg, 2003). First, there are no randomized studies proving its ef¬cacy in
preventing thromboembolic complications during severe OHSS. Furthermore,
in some clinical scenarios, thromboembolism still occurs despite giving heparin
(Hortskamp et al., 1996; Todros et al., 1999; Cil et al., 2000). Despite these
important reservations from Delvigne and Rozenberg (2003), I recommend
giving heparin or Lovenox for patients with severe OHSS.
I would like to separate the issue of severity of OHSS from thromboem-
bolism because of the prevalence of intrinsic coagulopathy that triggers
the problem even in moderate cases. While I have advocated a more liberal
policy for prophylaxis, others have followed that lead but, unfortunately,
had to operate on ruptured ectopic pregnancies in anticoagulated patients.
206 TREATMENT OF OVARIAN HYPERSTIMULATION SYNDROME




Therefore, thromboembolism will remain a dif¬cult complication to prevent
and may complicate the outcome.


Antibiotic Treatment
Infections are not uncommon in the treatment of OHSS because of frequent
catheterizations, venipuncture, transvaginal aspiration of ascitic ¬‚uid and
pleural drainage (Abramov et al., 1998a, 1999b). Furthermore, hypoglobuline-
mia is present in severe cases. Preoperative antibiotic prophylaxis is highly
recommended.


Immunoglobulin Replacement Therapy
Immuonoglobulin concentrations, speci¬cally IgG and IgA, are signi¬cantly
lower in the plasma of patients with severe OHSS. Both IgG and IgA levels
increase as patients clinically improve. Ascitic ¬‚uid contains high levels of
IgG but moderate levels of IgA and negligible IgM levels. Severe OHSS
is characterized by hypogammaglobulinemia that is attributed to leakage of
medium molecular weight immunoglobulins such as IgG and IgA into the
peritoneal cavity (Abramov, 1999a). Patients with nephrotic syndrome that
have hypogammaglobulinemia tend to develop infections that progress rapidly
and may result in death despite antibiotic treatment. Immunoglobulin
replacement therapy decreases bacterial infections in such patients. In light
of these favorable results, Abramov et al. (1999a) recommend prophylactic
immunoglobulin replacement therapy in patients with severe OHSS.
However, this intervention still awaits further evaluation (Delvigne and
Rozenberg, 2003).


Diuretics
Diuretic therapy without prior volume expansion may prove detrimental, by
further contracting the intravascular volume, thereby worsening hypotension
and its sequelae (Rizk et al., 1990a; Rizk and Aboulghar, 1991). Diuretics will
increase blood viscosity and increase the risk of venous thrombosis (Rizk and
Nawar, 2004; Rizk and Abdalla, 2006). Diuretics should used in the
management of pulmonary edema. Other authorities have used an albumin-
lasix chase protocol with success (Navot et al., 1992). I have not used that
protocol but their published experience should be consulted by the interested
clinician.


Dopamine
The use of dopamine has been successful in the treatment of oliguria associated
with severe OHSS (Ferraretti et al., 1992; Tsounado et al., 2003). This is usually
carried out in the intensive care setting, which will be discussed below.
207
INTENSIVE CARE TREATMENT OF PATIENTS WITH SEVERE OHSS




Indomethacin
Indomethacin has been investigated as an inhibitor of prostaglandin synthesis
that might play a role in the pathophysiology of OHSS. Schenker and Polishuk
(1976) demonstrated that indomethacin could prevent ¬‚uid shifts in ascites
and pleural effusion. However Pride et al. (1986) demonstrated that ascites
formation is not suppressed by indomethacin in experimental animal studies
(in the rabbit). In clinical practice, Katz et al. (1984) observed clinical
improvement by using indomethacin; however, a few years later, Borenstein
et al. (1989) from the same group found no clinical improvement in ascites
formation by using indomethacin in severe OHSS patients. Furthermore,
oliguria and renal failure have been attributed to indomethacin in cases of
OHSS in the absence of hypovolemia, due to its interference with renal
perfusion (Balasch et al., 1990).



INTENSIVE CARE TREATMENT OF PATIENTS WITH
SEVERE OHSS

Patients with renal failure, thromboembolism or adult respiratory distress
syndrome should be admitted to intensive care for treatment (Rizk and Nawar,
2004; Rizk and Aboulghar, 1999, 2005).


Patients with Renal Compromise

Dopamine
Dopamine has been used in oliguric patients with severe OHSS, resulting in
signi¬cant improvement in renal function (Ferraretti, 1992; Tsunoda et al.,
2003). Dopamine produces its renal effect by increasing renal blood ¬‚ow and
glomerular ¬ltration. This is accomplished via stimulation of the dopaminergic
receptors present in the vascular kidney (Felder et al., 1984). The rationale for
treating oliguric patients with dopamine is to avoid ¬‚uid and salt retention and
to prevent acute renal failure. Dopamine therapy should be given cautiously
and under strict observation.
Ferraretti et al. (1992) reported on the treatment of seven patients with
severe OHSS following gonadotrophin stimulation for IVF or GIFT using low
doses of dopamine by peripheral infusion. Management of the seven patients
consisted of bed rest, restriction of ¬‚uid intake to 500 ml/day, and daily
monitoring of urine output, abdominal girth and weight. In addition,
biochemical and hematological clotting factors were measured daily in the
pregnant women. Serum hCG was measured every two days and the patients
were given a protein z- and salt-rich diet in order to increase oncotic and
osmotic blood pressure. Dopamine treatment commenced within 10 h of
hospital admission using an intravenous infusion pump, which strictly
controlled the dosage of dopamine. The dopamine dosage used by the authors
208 TREATMENT OF OVARIAN HYPERSTIMULATION SYNDROME




was 4.32 mg/kg per 24 h. The reason for choosing this dosage was to produce
dilatation of renal vessels and increased renal blood ¬‚ow without affecting the
systemic blood pressure and pulse rate (Kirshon et al., 1988). Dopamine
treatment was continued until there was complete resolution of ascites. In the
¬ve patients who were pregnant, dopamine treatment was required for 9 to
22 days. The duration of treatment was related to the magnitude of the
increase of hCG. It was longest (18À22 days) in patients with triplets, shortest
(9À10 days) in patients with a singleton pregnancy and intermediate (14 days)
for patients with twins. In the two non-pregnant women, dopamine was only
required for seven days. Albumin or plasma expanders were only administered
if required, and anticoagulants were given to prevent thromboembolism if
clotting factors were abnormal.
Tsunoda et al. (2003) reported on 27 patients, hospitalized because of
OHSS and refractory to the initial therapy with intravenous albumin, who were
treated with docarpamine. A 750-mg tablet of docarpamine was taken every 8 h.
In 19 (86.4%) out of 22 patients, clinical symptoms associated with ascites
gradually improved after administrating docarpamine. Moreover, there were
no major adverse effects of docarpamine in this study. These ¬ndings indicate
that oral docarpamine administration could be one of the options in the
management of patients with OHSS using dopamine therapy.


Invasive Hemodynamic Monitoring
Invasive hemodynamic monitoring (of central venous pressure and pulmonary
artery pressures) may be needed in critical cases in which volume expanders are
being employed (Kirshon et al., 1988; Navot et al., 1992). The contracted
intravascular volume has been associated with a low central venous pressure
(Kirshon et al., 1988). Hemodialysis may be necessary once frank renal failure
ensues.


Pleurocentesis and Treatment of Pulmonary Complications
Pleural effusion was observed in 21% of 128 cases in a Belgian multi-center
conducted by Delvigne et al. (1993). Evaluation and treatment of patients with
severe OHSS complaining of dyspnea includes physical examination, chest
ultrasound, X-ray and arterial blood gases. It is essential to evaluate accurately
any pulmonary complications that may result in hypoxia. Serial arterial blood
gas measurements should be monitored, and if a pulmonary embolus is
suspected, a spiral CT scan or ventilation perfusion scan should be performed.
Pulmonary compromise should be treated with oxygen supplementation,
and the criteria for assisted ventilation should be reviewed (Whelan and
Vlahos, 2000). A dramatic improvement in the clinical status of these patients

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